Transporter peptides and application thereof

Abstract

The present invention relates to transporter peptides that can bind to a transferrin receptor (TfR). The transporter peptides can be conjugated covalently or noncovalently to an effector agent to form a transporter peptide conjugate, or a nucleic acid encoding the transporter peptides and an effector agent is expressed to form a recombinant transporter peptide conjugate. The transporter peptide conjugate and the recombinant transporter peptide conjugate deliver the effector agent to a target by binding to a TfR. Binding of the transporter peptides to transferrin receptors on cells of a tissue barrier induces transcytosis of the cells, thereby transporting the transporter peptide conjugate across the tissue barrier. The transporter peptides can serve as a drug delivery system and used for treatment of central nervous system (CNS) diseases.

1 . A transporter peptide, consisting of a sequence of SEQ ID NO: 1, and the transporter peptide being able to bind to a transferrin receptor (TfR). 
     
     
         2 . The transporter peptide of  claim 1 , wherein the sequence of the transporter peptide is selected from the group consisting of SEQ ID NO: 2 to SEQ ID NO: 30 and variant sequences at least 70% homologous to one of SEQ ID NO: 2 to SEQ ID NO: 30 and being able to bind to the transferrin receptor. 
     
     
         3 . A nucleic acid encoding the transporter peptide of  claim 1 . 
     
     
         4 . The nucleic acid of  claim 3 , wherein the nucleic acid is deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). 
     
     
         5 . A vector, comprising a nucleic acid encoding the transporter peptide of  claim 1 . 
     
     
         6 . The vector of  claim 5 , wherein the vector is an adeno-associated virus (AAV) vector. 
     
     
         7 . The vector of  claim 5 , further comprising a nucleic acid encoding an effector agent. 
     
     
         8 . The vector of  claim 7 , wherein the effector agent is at least one selected from the group consisting of peptides, proteins, antibodies, viral particles, liposomes, endosomes, exosomes, ligands, eukaryotic cells, prokaryotic cells, and microspheres. 
     
     
         9 . A recombinant transporter peptide conjugate, which is expressed by a vector comprising a nucleic acid encoding the transporter peptide of  claim 1  and a nucleic acid encoding an effector agent. 
     
     
         10 . A recombinant host cell, comprising at least one component selected from the group consisting of
 the transporter peptide of  claim 1 ;   a nucleic acid encoding the transporter peptide of  claim 1 ; and   a vector comprising a nucleic acid encoding the transporter peptide of  claim 1 .   
     
     
         11 . A transporter peptide conjugate, consisting of the transporter peptide of  claim 1  and an effector agent, and the effector agent being covalently or non-covalently conjugated to the transporter peptide. 
     
     
         12 . transporter peptide conjugate of  claim 11 , wherein the effector agent is at least one selected from the group consisting of siRNA, shRNA, microRNA, double-stranded RNA, single-stranded RNA, DNA, oligonucleotides, aptamers, genes, peptides, proteins, antibodies, small chemical molecules, large chemical molecules, viral particles, liposomes, endosomes, exosomes, nanoparticles, lipid nanoparticle, dendrimers, ligands, eukaryotic cells, prokaryotic cells, microspheres, nanogels, and bionanocapsules. 
     
     
         13 . A composition, comprising at least one selected from the group consisting of
 the transporter peptide of  claim 1 ;   a recombinant transporter peptide conjugate expressed by a vector comprising a nucleic acid encoding the transporter peptide of  claim 1  and a nucleic acid encoding an effector agent; and   a transporter peptide conjugate consisting of the transporter peptide of  claim 1  and an effector agent covalently or non-covalently conjugated to the transporter peptide.   
     
     
         14 . The composition of  claim 13 , further comprising a pharmaceutically acceptable carrier. 
     
     
         15 . A method of transporting the composition of  claim 13  to a target, the method comprising binding the transporter peptide, the transporter peptide of the recombinant transporter peptide conjugate, or the transporter peptide of the transporter peptide conjugate to a transferrin receptor. 
     
     
         16 . The method of  claim 15 , wherein the composition has to be transported across a tissue barrier to arrive at the target, and the transferrin receptor is located on a cell of the tissue barrier. 
     
     
         17 . The method of  claim 16 , wherein the tissue barrier is one of a blood-brain barrier (BBB), a mucosal barrier, and a gastrointestinal barrier. 
     
     
         18 . The method of  claim 17 , wherein binding of the transporter peptide of the composition, the transporter peptide of the transporter peptide conjugate of the composition, or the transporter peptide of the recombinant transporter peptide conjugate of the composition to the transferrin receptor induces transcytosis of the cells, thereby transporting the composition across the tissue barrier to arrive at the target. 
     
     
         19 . The method of  claim 15 , wherein the target is a cell expressing the transferrin receptor, and the transferrin receptor is located on the target. 
     
     
         20 . The method of  claim 15 , wherein the target is in vivo or in vitro. 
     
     
         21 . A method of transporting an effector agent across a tissue barrier of a subject, comprising administering to the subject a recombinant transporter peptide conjugate expressed by a vector comprising a nucleic acid encoding the transporter peptide of  claim 1  and a nucleic acid encoding an effector agent; or
 a transporter peptide conjugate consisting of the transporter peptide of  claim 1  and an effector agent covalently or non-covalently conjugated to the transporter peptide. 
 
     
     
         22 . The method of  claim 21 , wherein the tissue barrier is one of a blood-brain barrier (BBB), a mucosal barrier, and a gastrointestinal barrier. 
     
     
         23 . The method of  claim 22 , wherein cells of the tissue barrier express transferrin receptors. 
     
     
         24 . The method of  claim 23 , wherein the transporter peptide binds to the transferrin receptor, and the binding of the transporter peptide to the transferrin receptor induces transcytosis of the cells, thereby transporting the transporter peptide and the effector agent across the tissue barrier. 
     
     
         25 . The method of  claim 21 , wherein the recombinant transporter peptide conjugate or the transporter peptide conjugate is administered to the subject by one of intradermal delivery, intramuscular delivery, subcutaneous delivery, intravenous delivery, intra-atrial delivery, intra-articular delivery, intraperitoneal delivery, parenteral delivery, oral delivery, rectal delivery, intranasal delivery, intrapulmonary delivery, and transdermal delivery. 
     
     
         26 . The method of  claim 21 , wherein the effector agent in the recombinant transporter peptide conjugate is at least one selected from the group consisting of peptides, proteins, antibodies, viral particles, liposomes, endosomes, exosomes, ligands, eukaryotic cells, prokaryotic cells, and microspheres. 
     
     
         27 . The method of  claim 21 , wherein the effector agent consisted in the transporter peptide conjugate is at least one selected from the group consisting of siRNA, shRNA, microRNA, double-stranded RNA, single-stranded RNA, DNA, oligonucleotides, aptamers, genes, peptides, proteins, antibodies, small chemical molecules, large chemical molecules, viral particles, liposomes, endosomes, exosomes, nanoparticles, lipid nanoparticle, dendrimers, ligands, eukaryotic cells, prokaryotic cells, microspheres, nanogels, and bionanocapsules. 
     
     
         28 . The method of  claim 21 , wherein the subject is a mammal. 
     
     
         29 . The method of  claim 28 , wherein the subject is a rodent or a human. 
     
     
         30 . A method of treating or preventing a central nervous system (CNS) disease, comprising administering a subject in need thereof a pharmaceutically effective amount of
 a recombinant transporter peptide conjugate expressed by a vector comprising a nucleic acid encoding the transporter peptide of  claim 1  and a nucleic acid encoding an effector agent; or   a transporter peptide conjugate consisting of the transporter peptide of  claim 1  and an effector agent covalently or non-covalently conjugated to the transporter peptide.   
     
     
         31 . The method of  claim 30 , wherein the effector agent in the recombinant transporter peptide conjugate or consisted in the transporter peptide conjugate is a therapeutic agent of the CNS disease. 
     
     
         32 . The method of  claim 30 , wherein the transporter peptide of the recombinant transporter peptide conjugate or the transporter peptide of the transporter peptide conjugate binds to a transferrin receptor on a cell of a tissue barrier of the subject, and the binding of the transporter peptide to the transferrin receptor induces transcytosis of the cell, thereby transporting the transporter peptide and the therapeutic agent of the CNS disease across the tissue barrier. 
     
     
         33 . The method of  claim 32 , wherein the tissue barrier is one of a blood-brain barrier (BBB), a mucosal barrier, and a gastrointestinal barrier. 
     
     
         34 . The method of  claim 30 , wherein the subject is a mammal. 
     
     
         35 . The method of  claim 34 , wherein the subject is a rodent or a human. 
     
     
         36 . The method of  claim 30 , wherein the recombinant transporter peptide conjugate or the transporter peptide conjugate is administered to the subject in need thereof by one of intradermal delivery, intramuscular delivery, subcutaneous delivery, intravenous delivery, intra-atrial delivery, intra-articular delivery, intraperitoneal delivery, parenteral delivery, oral delivery, rectal delivery, intranasal delivery, intrapulmonary delivery, and transdermal delivery. 
     
     
         37 . The method of  claim 30 , wherein the CNS disease is one of Alzheimer's disease (AD), Parkinson's disease (PD), cerebrovascular accidents (CVA), ascular-related dementia, Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE), Traumatic Brain Injury (TBI), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington's chorea, and spinal muscular atrophy (SMA). 
     
     
         38 . The recombinant transporter peptide conjugate of  claim 9 , wherein the effector agent is at least one selected from the group consisting of peptides, proteins, antibodies, viral particles, liposomes, endosomes, exosomes, ligands, eukaryotic cells, prokaryotic cells, and microspheres. 
     
     
         39 . The composition of  claim 13 , wherein the effector agent in the recombinant transporter peptide conjugate is at least one selected from the group consisting of peptides, proteins, antibodies, viral particles, liposomes, endosomes, exosomes, ligands, eukaryotic cells, prokaryotic cells, and microspheres. 
     
     
         40 . The composition of  claim 13 , wherein the effector agent consisted in the transporter peptide conjugate is at least one selected from the group consisting of siRNA, shRNA, microRNA, double-stranded RNA, single-stranded RNA, DNA, oligonucleotides, aptamers, genes, peptides, proteins, antibodies, small chemical molecules, large chemical molecules, viral particles, liposomes, endosomes, exosomes, nanoparticles, lipid nanoparticle, dendrimers, ligands, eukaryotic cells, prokaryotic cells, microspheres, nanogels, and bionanocapsules. 
     
     
         41 . The method of  claim 30 , wherein the effector agent in the recombinant transporter peptide conjugate is at least one selected from the group consisting of peptides, proteins, antibodies, viral particles, liposomes, endosomes, exosomes, ligands, eukaryotic cells, prokaryotic cells, and microspheres. 
     
     
         42 . The method of  claim 30 , wherein the effector agent consisted in the transporter peptide conjugate is at least one selected from the group consisting of siRNA, shRNA, microRNA, double-stranded RNA, single-stranded RNA, DNA, oligonucleotides, aptamers, genes, peptides, proteins, antibodies, small chemical molecules, large chemical molecules, viral particles, liposomes, endosomes, exosomes, nanoparticles, lipid nanoparticle, dendrimers, ligands, eukaryotic cells, prokaryotic cells, microspheres, nanogels, and bionanocapsules.